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Left to right: Matthew Nguyen (BME PhD candidate) and Professor Warren Chan (BME found that about 45% of nanoparticles that accumulate in tumours end up exiting them. (Photos: submitted)

Researchers at the University of Toronto have developed a new theory to explain how nanoparticles enter and exit the tumours they are meant to treat, potentially rewriting an understanding of cancer nanomedicine that has guided research for nearly four decades.

The Enhanced Permeability and Retention (EPR) effect, a concept largely unchallenged since the mid-1980s, posits that nanoparticles enter a tumour from the bloodstream through gaps between the endothelial cells that line its blood vessels — and then become trapped in the tumour due to dysfunctional lymphatic vessels.

“The retention aspect of the EPR theory is contingent on the lymphatic vessel cavity being too small for nanoparticles to exit, thereby helping nanoparticles that carry cancer-fighting drugs to stay in the tumours,” says Matthew Nguyen, a PhD student in the Institute of Biomedical Engineering at the Faculty of Applied Science & Engineering and the Donnelly Centre for Cellular and Biomolecular Research,

“But we found around 45% of nanoparticles that accumulate in tumours will end up exiting them.”

Nguyen, who is a member of the lab of Professor Warren Chan (BME), is the lead author on a new study that challenges the long-standing theory that was recently published in the journal Nature Materials. The researchers’ findings help explain why treatments based on the EPR effect are failing in clinical trials, building on earlier research from the Chan lab that showed less than 1% of nanoparticles actually reach tumours.

Schematic of nanoparticle exit via the intratumoural lymphatic vessels. Nanoparticles in the tumour move towards the lymphatic vessel, cross the vessel wall and drain into the vessel lumen (Image: Nguyen, L.N.M., Lin, Z.P., Sindhwani, S. et al.)

The researchers found that, contrary to the EPR effect, nanoparticles can leave tumours through their lymphatic vessels. The exit method for a nanoparticle depends on its size, with larger ones (50-100 nanometres wide) more likely to leave through lymphatic vessels in the tumours, and smaller ones (up to 15 nanometres wide) more likely to leave through lymphatic vessels surrounding the tumours.

In rare cases, nanoparticles will exit through blood vessels.

Nanoparticle exit from tumours occurs through spaces in the lymphatic vessel walls and transport vesicles that carry them across these walls. The researchers showed that nanoparticles will re-enter the bloodstream following lymphatic drainage, and hypothesized that these nanoparticles will eventually return to the tumour for another opportunity to treat it.

Disproving the EPR effect was no easy feat. The Chan lab spent six years working to understand why nanoparticles do not accumulate in tumours effectively. Prior to this study, the lab focused on how nanoparticles enter tumours in the first place. Through this and other studies, the lab developed a competing theory to the EPR effect, called the Active Transport and Retention (ATR) principle.

Nguyen noted that the field of nanomedicine has evolved since the publication of the nanoparticle entry study in 2020. “We got more pushback from other researchers on that study compared to this one,” he says. “People have started to accept that the EPR effect is flawed.”

With nearly half of accumulated nanoparticles exiting tumours, mostly through lymphatic vessels, future research could address this issue through nanoparticle treatments that prevent lymphatic drainage.

“We are excited to have a better understanding of the nanoparticle tumour delivery process,” says Chan. “The results of these fundamental studies on nanoparticle entry and exit will be important for engineering nanoparticles to treat cancer.”

The study’s findings, if applied across the field of cancer nanomedicine, promise a new direction to improve our understanding of how nanoparticles can be used to treat tumours.

“Trying to translate cancer nanomedicine to the clinic is like working with a black box — some drugs work, some don’t, and it’s difficult to know why,” says Gang Zheng, associate research director at the Princess Margaret Cancer Centre and a professor of medical biophysics in U of T’s Temerty Faculty of Medicine who was not involved in the study.

“Chan’s dedication to better understanding the mechanisms of nanoparticle uptake and exit is shining light on these processes to help make our translation efforts more efficient and successful.”

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